Two related physiological conditions are ischemia and hypoxia. Ischemia refers to an inadequate flow of blood to a part of the body, caused by constriction or blockage of the blood vessels supplying it, and hypoxia is a shortage of oxygen, which may be the result of an ischemic condition, or may be the result of environmental and other causes.
There are a number of conditions in which ischemia is a factor. Ischemia is a feature of heart diseases, transient ischemic attacks, cerebrovascular accidents, ruptured sensitive to inadequate blood supply. Ischemia in brain tissue, for example due to stroke or head injury, causes a process called the ischemic cascade to be unleashed, in which proteolytic enzymes, reactive oxygen species, and other harmful chemicals damage and may ultimately kill brain tissue. Insufficient blood supply causes tissue to become hypoxic. In very aerobic tissues such as heart and brain, at body temperature necrosis due to ischemia usually takes about 3-4 minutes before becoming irreversible.
Restoration of blood flow after a period of ischemia can actually be more damaging than the ischemia. Reintroduction of oxygen causes a greater production of damaging free radicals as well as allowing, via removal of the extracellular acidotic conditions, influx of calcium and thus calcium overloading. The absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than restoration of normal function. Overall this results in reperfusion injury which can result in potentially fatal cardiac arrhythmias, also necrosis can be greatly accelerated.
The damage of reperfusion injury is due in part to the inflammatory response of damaged tissues. White blood cells, carried to the area by the newly returning blood, release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage. The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane. Damage to the cell's membrane may in turn cause the release of more free radicals. Such reactive species may also act indirectly in redox signaling to turn on apoptosis. Leukocytes may also build up in small capillaries, obstructing them and leading to more ischemia.
Reperfusion injury plays a part in the brain's ischemic cascade, which is involved in stroke and brain trauma. Similar failure processes are involved in brain failure following reversal of cardiac arrest. Reperfusion injury is also associated with graft transplantation.
A common feature of tissue hypoxia is increased cellular reactive oxygen species (ROS), macromolecular damage and permanent cellular injury. For example, hypoxic liver injury from a variety of etiologies including liver congestion, toxins, bile acids, cancer and ischemia-reperfusion after liver resection or transplantation is in part mediated by oxidative stress. The liver requires a constant supply of oxygen to maintain adequate energy production for hepatocyte homeostasis and survival. Therefore, hepatocytes have evolved a number of protective mechanisms in order to mitigate oxidative injury. The net result of overwhelming injury when this process fails is hepatocyte death and liver fibrosis leading to progressive disease.
Compositions and methods that alleviate the adverse effects of hypoxia and ischemia, in particular injury resulting from ischemia reperfusion, are of great interest for clinical and other uses. The present invention addresses this issue.